WO2018010651A1 - Procédé de fabrication d'acide obéticholique et de ses intermédiaires - Google Patents

Procédé de fabrication d'acide obéticholique et de ses intermédiaires Download PDF

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Publication number
WO2018010651A1
WO2018010651A1 PCT/CN2017/092554 CN2017092554W WO2018010651A1 WO 2018010651 A1 WO2018010651 A1 WO 2018010651A1 CN 2017092554 W CN2017092554 W CN 2017092554W WO 2018010651 A1 WO2018010651 A1 WO 2018010651A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
group
hydrogen
borohydride
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PCT/CN2017/092554
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English (en)
Chinese (zh)
Inventor
张顺吉
王生
刘路
田伟伟
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江苏恒瑞医药股份有限公司
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Priority to CN201780004218.6A priority Critical patent/CN108602850B/zh
Priority to CA3027761A priority patent/CA3027761A1/fr
Publication of WO2018010651A1 publication Critical patent/WO2018010651A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a preparation method of oleic acid and an intermediate thereof.
  • Obicholic acid (as shown in formula I), chemical name 6 ⁇ -ethyl-3 ⁇ , 7 ⁇ -dihydroxy-5 ⁇ -cholanoic acid, is a semi-synthetic chenodeoxycholic acid derivative used to treat the portal vein Hypertension and liver disease, including primary biliary cirrhosis, bile acid diarrhea, nonalcoholic steatohepatitis.
  • Obecholic acid acts by activating FXR receptors, a nuclear receptor that is expressed primarily in the liver, intestines, and kidneys. It regulates the expression of genes involved in bile acids, fats, and glucose metabolism, and regulates immune response. Activation of FXR inhibits bile acid synthesis and prevents toxic reactions caused by excessive accumulation of bile acids.
  • WO2002072598 discloses for the first time the preparation method of oleic acid (as shown below), which is obtained by direct alkylation of compound XIV with iodoethane under strong basic conditions to obtain compound XV, which is obtained by reduction and carboxyl deprotection of compound XV.
  • Abecholic acid due to the poor selectivity and low yield of direct alkylation with iodoethane, it is difficult to achieve amplification synthesis in this synthesis process.
  • WO2006122977 has improved the above synthesis process (as shown below) by converting compound VIII into a silicon-based protected enol compound IX, compound IX and acetaldehyde are condensed and dehydrated to obtain compound X, and compound X is first hydrolyzed to obtain XI. Further, the compound XII is obtained by hydrogenation reduction of palladium carbon under basic conditions, and the compound XII is reduced by a carbonyl group to obtain oleic acid. Although the synthesis process can achieve amplification synthesis, the yield of the hydrogenation reduction step is low, resulting in a low yield of the final product.
  • WO2016045480 discloses a novel synthesis method of oleic acid by finally protecting the hydroxyl group of the compound (XIa) and then hydrogenating the reaction to finally obtain oleic acid.
  • the yield of the synthesis process is increased, the reaction has difficulty in the amplification process, the reaction yield is lowered, the impurities are generated, and the separation and purification are difficult, resulting in the presence of a part of impurities in the final product oleic acid which cannot be removed, and the purification is difficult.
  • the invention provides a process for the preparation of a compound of formula V, which comprises preparing a compound V by hydrogenation of a compound of formula VI in the presence of an acidic material and a catalyst,
  • R 1 is hydrogen or a carboxy protecting group, preferably hydrogen or C 1-10 alkyl, more preferably hydrogen, methyl or ethyl;
  • R 2 is C 1-5 alkyl, preferably methyl;
  • R 3 It is a hydrogen or hydroxy protecting group, preferably hydrogen or methoxymethyl.
  • the acidic material may be a protic acid or a Lewis acid, preferably an organic or inorganic acid, more preferably a C 1-5 alkyl acid, most preferably acetic acid or formic acid.
  • the catalyst may be a catalyst commonly used in catalytic hydrogenation, preferably palladium carbon, PtO 2 or Raney nickel. The hydrogenation reaction is preferably carried out at a pressure between 1 and 3 atmospheres.
  • Another aspect of the present invention provides a process for the preparation of oleic acid comprising the above-described step of preparing a compound of formula V wherein R 2 is a methyl group.
  • R 1 is a carboxy protecting group, preferably a methyl or ethyl group; and R 3 is hydrogen;
  • R 1 is hydrogen and R 3 is hydrogen.
  • R 1 is a carboxy protecting group and R 3 is hydrogen
  • the 3 ⁇ -hydroxy group of compound V can be further protected to a compound of formula IV wherein R 5 is a hydroxy protecting group, preferably a methoxymethyl group.
  • the compound of formula IV can be further hydrolyzed under basic conditions to give a compound of formula III.
  • the compound of formula III can be further reduced by a reducing agent to give a compound of formula II, wherein the reducing agent is preferably a borohydride, more preferably sodium borohydride.
  • the compound of formula II can be further dehydroxylated to give the oleic acid.
  • the method of preparation further comprises the step of heat treating a compound selected from the group consisting of compounds V, IV, III, the heat treatment comprising heating the compound under basic conditions, preferably at a temperature of from 95 to 105 °C.
  • the heat treatment step may be carried out after any one of the steps of preparing the compound V, IV or III, and the heat treatment method is a method disclosed in the prior art, that is, heating the product under alkaline conditions, specifically, reacting The product is heated under the alkaline condition at a temperature of 95-105 ° C for an hour to make the 6- ⁇ -ethyl epimerization to 6- ⁇ -ethyl.
  • the reaction in this step is stable, the conversion rate is high, and the yield is basically more than 90 percent.
  • the compound of formula V may be further reduced by a reducing agent to obtain oleic acid, optionally further comprising the step of heat treating the compound of formula V, wherein the reducing agent is preferably a borohydride, more preferably Sodium borohydride, the heat treatment comprising heating the compound under alkaline conditions, preferably at a temperature of from 95 to 105 °C.
  • the reducing agent is preferably a borohydride, more preferably Sodium borohydride
  • Another aspect of the invention also provides a method for preparing oleic acid, comprising the steps of:
  • a compound of the formula VIb is hydrogenated in the presence of an acidic material and a catalyst to produce a compound of the formula Vb;
  • R 4 is a carboxy protecting group, preferably a methyl or ethyl group
  • R 5 is a hydroxy protecting group, preferably a methoxymethyl group
  • the acidic medium is preferably formic acid or acetic acid
  • the catalyst is preferably palladium carbon
  • the borohydride The material is preferably sodium borohydride, and the heat treatment comprises heating the product under basic conditions, preferably at a temperature of from 95 to 105 °C.
  • Another aspect of the invention also provides a method for preparing oleic acid, comprising the steps of:
  • the acidic medium is preferably formic acid or acetic acid;
  • the catalyst is preferably palladium carbon;
  • the borohydride boron hydrogen Sodium the heat treatment comprising heating the compound of formula IIc under basic conditions, preferably at a temperature of from 95 to 105 °C.
  • a bond Configuration is not specified, ie key Can be or Or both with Two configurations.
  • the hydroxy protecting group of the present invention is a suitable group for hydroxy protection known in the art, see the hydroxy protecting group in the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GM Wuts).
  • the hydroxy protecting group may be a (C 1-10 alkyl or aryl) 3 silane group, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethyl Silyl, tert-butyldiphenylsilyl, etc.; may be a C 1-10 alkyl or substituted alkyl group, preferably an alkoxy or aryl substituted alkyl group, more preferably a C 1-6 alkoxy substituted C a 1-6 alkyl or phenyl substituted C 1-6 alkyl group, most preferably a C 1-4 alkoxy substituted C 1-4 alkyl group, for example: methyl, tert-butyl,
  • Carboxylic acid protecting group is a suitable group for carboxylic acid protection known in the art, see the carboxylic acid protecting group in the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GM Wuts), As an example, preferably, the carboxylic acid protecting group may be a substituted or unsubstituted C 1-10 linear or branched alkyl group, a substituted or unsubstituted C 2-10 linear or branched alkenyl group.
  • alkynyl substituted or unsubstituted C 3-8 cyclic alkyl, substituted or unsubstituted C 5-10 aryl or heteroaryl, or (C 1-8 alkyl or aryl) 3 silane
  • a straight or branched alkyl group of C 1-6 is preferred, and a linear or branched alkyl group of C 1-4 is more preferred.
  • Alkyl means a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 20 carbon atoms. Preference is given to alkyl groups having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl or pentyl groups and the like. More preferred are lower alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or tert-butyl, pentyl, heptyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkoxy, halogen, hydroxy, nitro, cyano, cycloalkyl, Heterocyclic group, aryl group, heteroaryl group, carbonyl group.
  • the compound IIa (4.4 kg) was dissolved in 50 liters of tetrahydrofuran, cooled to 0 ° C, 40 liters of 4N aqueous hydrochloric acid solution was added, the temperature was raised to 20 ° C, and the reaction was carried out for 8 hours, and 40 liters of ethyl acetate was added thereto, and the extract was concentrated and analyzed. Crystallization, filtration and drying gave 3.8 kg of oleic acid in a yield of 95% and HPLC purity of 98.4%.
  • Example 3 According to the method of Example 3 in WO2016045480, the compound IId (1.96 kg) was dissolved in 20 L of tetrahydrofuran, the reaction solution was cooled to 0 ° C, 15 liters of 4N aqueous hydrochloric acid solution was added, and the mixture was heated to 20 to 30 ° C for 8 hours, and TLC showed impurities. The reaction mixture was concentrated under reduced pressure. The residue was evaporated. The yield was 58%, and the HPLC purity was 89.6%.

Abstract

La présente invention concerne un procédé de fabrication d'un acide obéticholique et d'un intermédiaire de celui-ci. L'invention concerne spécifiquement un procédé de fabrication d'un composé représenté par la formule V. Le procédé comprend: en utilisant un composé représenté par la formule VI et en effectuant une réaction d'hydrogénation en présence d'une substance acide et d'un catalyseur pour obtenir le composé représenté par la formule V, et l'utilisation du composé représenté par la formule V pour fabriquer l'acide obéticholique. Le procédé présente les avantages de conditions de réaction modérées, de rendement élevé, de peu de sous-produits, de facilité de fonctionnement et d'applicabilité dans une production à grande échelle.
PCT/CN2017/092554 2016-07-13 2017-07-12 Procédé de fabrication d'acide obéticholique et de ses intermédiaires WO2018010651A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201780004218.6A CN108602850B (zh) 2016-07-13 2017-07-12 一种奥贝胆酸及其中间体的制备方法
CA3027761A CA3027761A1 (fr) 2016-07-13 2017-07-12 Procede de fabrication d'acide obeticholique et de ses intermediaires

Applications Claiming Priority (2)

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CN201610551378 2016-07-13
CN201610551378.X 2016-07-13

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CN (1) CN108602850B (fr)
CA (1) CA3027761A1 (fr)
TW (1) TW201802103A (fr)
WO (1) WO2018010651A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019145977A1 (fr) * 2018-01-25 2019-08-01 Msn Laboratories Private Limited, R&D Center PROCÉDÉ DE PRÉPARATION DE L'ACIDE 3α,7α-DIHYDROXY6α-ÉTHYL-5β-CHOLAN-24-OÏQUE
CN112898369A (zh) * 2019-12-04 2021-06-04 博瑞生物医药（苏州）股份有限公司 用于制备奥贝胆酸的方法

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CN116178473A (zh) * 2018-12-10 2023-05-30 江西青峰药业有限公司 一种奥贝胆酸的制备方法

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WO2006122977A2 (fr) * 2005-05-19 2006-11-23 Erregierre S.P.A. Procede d'elaboration d'acide 3?(?)-7?(?)-dihydroxy-6?(?)-alkyle-5?-cholanique
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CN106008639A (zh) * 2016-03-11 2016-10-12 深圳市塔吉瑞生物医药有限公司 用于预防或治疗fxr-介导疾病的胆烷酸化合物
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Cited By (3)

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Publication number Priority date Publication date Assignee Title
WO2019145977A1 (fr) * 2018-01-25 2019-08-01 Msn Laboratories Private Limited, R&D Center PROCÉDÉ DE PRÉPARATION DE L'ACIDE 3α,7α-DIHYDROXY6α-ÉTHYL-5β-CHOLAN-24-OÏQUE
US11434256B2 (en) 2018-01-25 2022-09-06 Msn Laboratories Private Limited, R&D Center Process for the preparation of 3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oic acid
CN112898369A (zh) * 2019-12-04 2021-06-04 博瑞生物医药（苏州）股份有限公司 用于制备奥贝胆酸的方法

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CA3027761A1 (fr) 2018-01-18
CN108602850B (zh) 2021-04-06
TW201802103A (zh) 2018-01-16
CN108602850A (zh) 2018-09-28

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